Lung Cancer

Faria Nasim, MD, Bruce F. Sabath, MD, George A. Eapen, MD*

KEYWORDS
 Lung cancer  Smoking  Screening  Staging  Chemotherapy

KEY POINTS
 Lung cancer is the leading cancer killer in the world.
 Smoking is the predominant risk factor, but other risk factors exist.
 Low-dose computed tomography for lung cancer screening improves mortality.
 Various modalities exist for diagnosis and staging of lung cancer.
 Treatment depends on several factors and is best guided by a multidisciplinary team to
determine the best approach for a given patient.

INTRODUCTION

Lung cancer is the world’s leading cause of cancer death.1 This is largely because it is
initially asymptomatic and typically discovered at advanced stages. Screening for lung
cancer by low-dose computed tomography (LDCT) has recently been shown to have a
mortality benefit, and implementation of this practice is growing. Once suspected,
lung cancer must be diagnosed and staged, and there are recent guidelines to aid
in this process. Treatment is determined by subtype and stage of cancer and there
are several personalized therapies that did not exist just a few years ago. This review
provides a broad outline of this disease, helping clinicians identify such patients and
familiarizing them with lung cancer care so they are better equipped to guide their pa-
tients along this challenging journey.

EPIDEMIOLOGY

Worldwide, lung cancer continues to be the most common cause of cancer death.1
Approximately 1.8 million new people were diagnosed in 2012, with 1.6 million fatal-
ities. It is estimated that, in 2018, the United States alone will have had more than
230,000 new cases, and that lung cancer will lead to more deaths than breast,

Disclosure Statement: The authors have no commercial or financial conflicts of interest nor any
relevant funding sources.
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Unit
1462, 1515 Holcombe Boulevard, Houston, TX 77030, USA
* Corresponding author.
E-mail address: geapen@mdanderson.org

Med Clin N Am 103 (2019) 463–473

https://doi.org/10.1016/j.mcna.2018.12.006 medical.theclinics.com
0025-7125/19/ª 2019 Elsevier Inc. All rights reserved.
464 Nasim et al

prostate, and colon cancers combined.2 Lung cancer is relatively rare before the fifth
decade of life; risk increases with age thereafter.2 Men are more affected than women.
Interestingly, although smoking is the exposure most closely tied to lung cancer (an
estimated 80%–90% of cases are caused by this), only approximately 15% of
smokers develop lung cancer, suggesting a genetic susceptibility.3 Smoking intensity
(eg, how many cigarettes per day) and lifetime duration affect risk proportionately.4 As
a corollary, smoking cessation reduces lung cancer risk. For patients who cannot quit
completely, even reducing the number of cigarettes smoked daily has a demonstrated
benefit.5 Generally speaking, any form of smoking exposure increases lung cancer
risk, including secondhand smoke and cigar and pipe smoking.6 The association of
marijuana is less clear due to conflicting results, and that of electronic cigarettes is
also uncertain, in part due to confounding from prior or concurrent cigarette use,
and the lack of long-term data.7 Asbestos exposure acts synergistically with tobacco
use, being associated with higher rates of lung malignancy than either risk factor
alone. Other risk factors include radon exposure and some forms of interstitial lung
disease. The presence of chronic obstructive lung disease and a family history are
also associated with lung cancer, even after adjustment for tobacco exposure.6

SCREENING

Until recently, no effective method of lung cancer screening was available. Several
studies have investigated the role of LDCT, the largest of which is the National Lung
Screening Trial (NLST), which included more than 50,000 patients and had longer
follow-up compared with other randomized controlled trials.8 Researchers demon-
strated a 20% reduction in lung cancer mortality by annual LDCT compared with chest
radiograph (CXR) with a decrease in overall mortality by 6.7%. A concern raised with
screening by LDCT is the high rate of benign nodules detected (more than 90% in
most studies). In the NLST, for example, approximately one-quarter of the scans
revealed nodules, with 96.4% of these being benign; a similarly high false-positive
rate was found in the CXR arm. Another concern with repeated LDCT screening tests
is accumulating radiation exposure. It is estimated that a single LDCT will expose a
patient to 1.5 mSv of radiation. The average total exposure for each NLST participant
over 3 years was approximately 8 mSv. By way of comparison, the average annual
dose provided by background radiation (in the United States) is 3 to 4 mSv.9 Even
with the high false-positive rates and radiation risks, available evidence indicates
that the reductions in cancer death brought about by screening outweigh the possible
risks. Based on these findings, the US Preventive Services Task Force recommends
lung cancer screening with LDCT in adults of age 55 to 80 years who have a 30
pack-year smoking history and are currently smoking or have quit within the past
15 years.10 Approximately 8 million Americans are eligible to receive annual screening
with LDCT using these criteria.11 The current National Comprehensive Cancer
Network (NCCN) Clinical Practice Guidelines in Oncology for Lung Cancer Screening
also considers it reasonable to use a statistical risk prediction model (https://brocku.
ca/lung-cancer-risk-calculator) to quantify lung cancer risk for individuals who do not
meet the NLST criteria but may be at similar risk to the NLST cohort.12 Because the
benefits of screening decrease at lower-risk thresholds, but the harms of screening
remain constant, it is challenging to determine the ideal balance of benefit and
harm, particularly as the impact of the benefit and harms can vary markedly with pa-
tient preferences.13 The American Thoracic Society/American College of Chest Physi-
cians policy statement on lung cancer screening provides guidelines for
implementation of a successful screening program that include structured reporting
 Lung Cancer 465

and a smoking cessation program. Screening should be discontinued once an individ-

ual has not smoked for 15 years or develops a health problem that substantially limits
life expectancy or the ability or willingness to have curative treatment.14

INCIDENTAL VERSUS SCREEN-DETECTED PULMONARY NODULE MANAGEMENT

There are important distinctions between nodules found incidentally and those found
on screening LDCT. The Fleischner Society guidelines are typically used for manage-
ment of incidental detected pulmonary nodules on computed tomography (CT). The
more recent guidelines revised in 2017 recommend longer intervals between scans
even for high-risk individuals with nodules >6 mm. To estimate high risk, the American
College of Chest Physicians intermediate-risk (5%–65% risk) and high-risk (>65% risk)
categories are combined into one category. High-risk factors include older age, heavy
smoking, larger nodule size, irregular or spiculated margins, and upper lobe location.
The NCCN clinical practice guidelines in oncology provide management recommen-
dations for screen-detected nodules. In 2018, the NCCN cutoff thresholds for lung
nodules were revised to reflect the Lung Imaging Reporting and Data System
(Lung-RADS) cutoffs. Lung-RADS is a structured decision-oriented reporting system
published in 2014 that aimed to reduce the false-positive result rate and suggest man-
agement recommendations based on estimated lung cancer risk.15 Table 1 summa-
rizes the current recommendations based on these guidelines.

CLINICAL MANIFESTATIONS

Occurring in approximately half of patients with lung cancer, a new cough in a smoker
or former smoker should raise concern for lung cancer. Recurrent pneumonia in the
same anatomic location or frequent exacerbations of chronic obstructive pulmonary
disease also should trigger concern for neoplasm as a root cause.18 Dyspnea is pre-
sent in approximately one-third to one-half of patients with lung cancer, and could be

Table 1
Guidelines for pulmonary nodule management

Recommended Follow-up, mo
Nodule type Size, mm Fleischner 201716 NCCN 201812 Lung-RADS 201417
Applicable All Incidental LDCT screening LDCT Screening
population
Solid <6 None for low risk, AS AS
12 mo optional
for high risk
6–8 6–12 mo, 18–24 mo 6 mo 6 mo, AS
>8 3 mo, PET, or 3 mo, PET, tissue 3 mo, AS
tissue sampling sampling for
high risk
Part solid <6 None AS AS
6 3–6 mo, every Based on size Based on size
12 mo  5 y of solid of solid
component component
Ground glass <6 None AS AS
6 6–12 mo, every AS AS up to 20 mm
24 mo until 5 y

Abbreviations: AS, annual screening; LDCT, low-dose computed tomography; Lung-RADS, lung im-
aging reporting and data system; NCCN, national comprehensive cancer network.
466 Nasim et al

due to direct malignant airway, or parenchymal or pleural involvement. Patients also

are at risk of developing pulmonary emboli, pneumothoraces, pleural effusions, and/
or pericardial effusions. Other less common symptoms include chest pain from
regional tumor invasion and hoarseness from involvement of the recurrent laryngeal
nerve. Hemoptysis is the presenting symptom in approximately one-quarter of pa-
tients with lung cancer and is rarely massive.19 Other manifestations of intrathoracic
spread are the superior vena cava syndrome, dysphagia, or arm/shoulder pain; these
are all due to mass effect on various structures. Patients also can present with symp-
toms from extrathoracic metastases. Often these are nonspecific, such as weight loss,
anorexia, and fatigue.18 Bone metastases are frequently painful; brain metastases can
be asymptomatic, although neurologic sequelae do manifest based on size and loca-
tion. Finally, paraneoplastic syndromes can occur, including the syndrome of inappro-
priate antidiuretic hormone, neurologic syndromes, such as Lambert-Eaton
myasthenic syndrome and cerebellar ataxia, or hypercalcemia from bone metastases
or secretion of parathyroid hormone–related protein.20
Box 1 reviews when a pulmonary consultation should be considered.

DIAGNOSIS AND STAGING

All patients with known or suspected non–small-cell lung cancer (NSCLC) should have
a thorough clinical evaluation and a CT chest with contrast.21 If both clinical evaluation
and CT scan are without extrathoracic abnormalities, a PET scan is recommended to
evaluate for metastases.9 Notably, a PET scan may not be required if the primary lung
lesion is a ground glass opacity or a peripheral nodule 3 cm or smaller, as these have a
low likelihood of metastasis, assuming negative intrathoracic nodal involvement on
CT.21 Such patients may proceed directly to curative-intent treatment immediately af-
ter tissue confirmation. For patients who do not clearly have very early or advanced
NSCLC, staging of intrathoracic lymph nodes is recommended. However, if the medi-
astinum is extensively infiltrated, invasive staging may not be necessary.21 When sam-
pling is needed, endobronchial ultrasound (EBUS)-guided bronchoscopic sampling is
recommended over surgical staging by mediastinoscopy. Direct comparison trials
have shown EBUS-guided sampling of thoracic lymph nodes to perform as well as
or better than surgical sampling while also being less invasive and having fewer com-
plications.22 However, if suspicion of nodal involvement remains after a negative result
by bronchoscopy, surgical confirmation should be performed.21 Given the previously
described complexities, it is advisable that any patient with suspected lung cancer be
referred to a pulmonologist, and multidisciplinary care is recommended.
Various methods for diagnosis and staging (bronchoscopic, surgical, and transtho-
racic) exist, and a pulmonologist can provide guidance for further steps as needed.

Box 1
Recommendations on when to call a pulmonary consultation

To determine a patient’s candidacy for lung cancer screening

To decide how to approach the diagnosis of a lung nodule (or if a diagnosis is necessary)
History of pneumonia that does not resolve completely (either symptomatically or
radiographically)
The presence of any pleural effusion, particularly if exudative without a clear etiology
Any patient with lung cancer with shortness of breath
Hemoptysis
 Lung Cancer 467

Table 2 summarizes the various diagnostic modalities along with their diagnostic
yield. Minimizing invasive procedures is desirable, such as attempting to diagnose
and stage with a single procedure if possible. For example, if a patient with a lung
mass has any sign of metastasis (eg, enlarged mediastinal lymph nodes, pleural effu-
sion, and adrenal mass), the highest-stage location should be sampled first, if feasible
and technically safe to do so.23 The reason is that the finding of lung cancer at a met-
astatic site would adequately provide both diagnostic and staging information. Finally,
the aforementioned diagnostic approaches apply largely to NSCLC rather than small-
cell lung cancer (SCLC). Current guidelines suggest that if SCLC is suspected (based
on certain characteristics, such as massive adenopathy, direct mediastinal invasion,
or the presence of a paraneoplastic syndrome, for example), then diagnosis should
be sought via the least-invasive method.23

BRIEF UPDATE ON THE EIGHTH EDITION TUMOR-NODE-METASTASIS

CLASSIFICATION OF LUNG CANCER

The eighth edition of the tumor-node-metastasis (TNM) classification for lung cancer
has some clinically important updates. There are 24 T descriptors and the “p” or “c”
T-stage designators correspond to the pathologic versus the clinical stage, respec-
tively. Size measurement in part-solid nodules uses the size of solid component for
clinical size, and size of invasive component for pathologic size. Tumor size itself is
a descriptor in all T categories and every centimeter increment in size affects prog-
nosis.28 To ensure accurate radiographic assessment of T stage, the International As-
sociation for the Study of Lung Cancer recommends that tumor size be measured in
the lung window. The new T categories are Tis, denoting carcinoma in situ (squamous
or adenocarcinoma), and T1a (mi), for minimally invasive adenocarcinoma. T2 and T3
endobronchial tumors have similar prognosis, even with total atelectasis and pneumo-
nitis. T3 with involvement of the diaphragm has been reclassified as a T4 tumor.29
For the N component, it is important to quantify nodal disease both clinically and
pathologically. Apart from keeping the seventh edition N descriptors as they are,
new subclass descriptors have been added for prospective testing and validation.
pN1a will denote involvement of single pN1 nodal station, whereas pN1b will be
assigned to involvement of multiple pN1 nodal stations. pN2a1 will be designated
for involvement of single pN2 nodal station without pN1 (skip pN2), and pN2a2 will

Table 2
Diagnostic modalities for tissue diagnosis of lung cancer and their yield

Diagnostic Modality Yield, %

Convex probe endobronchial ultrasound 94.5
transbronchial needle aspiration24
Peripheral bronchoscopy with radial probe25 53–84
Electromagnetic navigation bronchoscopy26 38–71
Computed tomography–guided 90
transthoracic needle aspiration27
Image-guided closed pleural biopsy23 75–88
Pleuroscopy with pleural biopsy23 95–97
Thoracentesis23 72
Conventional bronchoscopy with 88
endobronchial biopsy, brushings,
and washings23
468 Nasim et al

be involvement of single pN2 nodal station with pN1. Last, pN2b will be involvement of
multiple pN2 nodal stations.
Finally, for the M component, number of metastases is more important than their
location. Cancers with multiple lesions are defined by disease pattern. For multiple pri-
mary tumors, 1 TNM is assigned for each tumor. These changes in the eighth edition of
the TNM classification of lung cancer aim to facilitate more homogeneous tumor clas-
sification and collection of prospective data to improve tumor stratification for future
research trials.30

TREATMENT

For early-stage lung cancer, surgical resection is the preferred treatment.31 The extent
of resection depends on the size and location of the tumor as well as the patient’s pre-
operative pulmonary reserve. Adjuvant chemotherapy is recommended for completely
resected stage II NSCLC but not usually stage I. Postoperative radiation is not recom-
mended except for incomplete resection. For those with early-stage NSCLC who are
not surgical candidates, stereotactic ablative body radiotherapy (SABR), can be
considered.32 Comparative studies are under way as to whether this is equivalent to
surgery in terms of long-term outcomes.33,34 An alternative to SABR is percutaneous
ablation for select peripheral tumors, but there is scant evidence of efficacy and a sub-
stantial pneumothorax rate.35 Transbronchial ablation may have certain advantages
and is currently in investigational stages.36
Stage III NSCLC encompasses a heterogeneous group of patients. Patients with
limited nodal (N1) involvement may be candidates for surgical resection upfront fol-
lowed by chemotherapy and/or radiation.37 Those with more advanced nodal (N2)
involvement may still be candidates for surgery, although usually only after induction
therapy because data have consistently shown better outcomes with this approach.38
Nevertheless, whether there is greater benefit from tri-modality therapy (surgery,
chemotherapy, radiation) versus chemo-radiation alone is still unclear, and further
studies of subgroups of patients with N2 disease are needed.38 Patients with most
advanced nodal (N3) involvement are not generally considered to be surgical
candidates.
For patients with stage IV NSCLC, chemotherapy with platinum-based (eg,
cisplatin, carboplatin) 2-drug, regimens is standard, but the past several years have
seen the significant additional therapies directed at specific driver mutations.39 As
such, efforts should be made to not only determine the histologic subtype but also
to obtain sufficient tissue for molecular analysis. Each institution has its own approach
to molecular testing, but typically, testing tumor tissue for epidermal growth factor re-
ceptor gene mutations, anaplastic lymphoma kinase gene rearrangements, reactive
oxygen species proto-oncogene-1 gene rearrangements, B-raf proto-oncogene point
mutations and KRAS proto-oncogene (KRAS) point mutations is recommended.37 The
presence of such genetic alterations can guide the choice of targeted therapies, as
they can predict responsiveness (or lack thereof) to certain agents. In addition, testing
for programmed death ligand-1 expression levels can be used to guide treatment with
certain immunotherapies. Indeed, the armamentarium against stage IV disease is
greater than it has ever been. This will all be managed by a medical oncologist, but
it is useful for the referring clinician to be familiar with the options. Table 3 summarizes
the commonly used molecular targeted therapies and immunotherapies currently
approved by the Food and Drug Administration.
Aside from systemic therapy, local treatment is sometimes needed in stage IV dis-
ease if a given metastatic focus is causing localized symptoms.37,40 Airway
 Lung Cancer 469

Table 3
Molecularly targeted therapies and immunotherapeutics currently approved by the Food and
Drug Administration

Lung Cancer Target Drug Type of Therapy

NSCLC The anti-programmed Nivolumab, Immunotherapy
death-1 (PD-1)/PD-ligand pembrolizumab,
1 pathway44 atezolizumab,
durvalumab, avelumab
Anti-cytotoxic T-lymphocyte- Ipilimumab,
associated antigen tremelimumab
4 (CTLA-4) pathway44
Epidermal growth factor Tyrosine kinase inhibitors: Molecular targeted
receptor (EGFR)145 erlotinib, gefitinib, therapy
afatinib, osimertinib
Anaplastic lymphoma Tyrosine kinase inhibitors:
kinase (ALK)1 46 crizotinib, ceritinib,
alectinib, brigatinib
B-raf proto-oncogene 47 Dabrafenib and trametinib
combination
Vascular endothelial growth Ramucirumab
factor (VEGF) receptor45
SCLC Mammalian target of Everolimus
rapamycin (mTOR)48
PD-1 pathway49 Nivolumab

Abbreviations: NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer.

obstruction by tumor may cause dyspnea, postobstructive pneumonia, or hemopty-

sis, for example, An interventional pulmonologist may be able to alleviate these symp-
toms and possibly improve performance status, thereby improving candidacy for
systemic therapy.41 Bone or brain metastases may undergo radiation therapy or
even surgical treatment in specific circumstances.40 Recurrent, symptomatic malig-
nant pleural effusions are usually best treated with tunneled pleural catheters or chem-
ical pleurodesis, but repeated thoracentesis is an alternative if a patient’s life
expectancy is very short.
SCLC is treated with a more simplified approach compared with NSCLC; all patients
receive systemic therapy.42 Those with confirmed limited stage disease also receive
radiation. Patients with extensive disease initially receive systemic therapy alone,
although palliative radiation can be given at sites in which tumor burden is causing
clinically significant symptoms. Surgical resection is reserved for fewer than 5% of
all SCLC where stage I disease is found and confirmed with invasive nodal staging
and PET scan.42 Even in these cases, adjuvant postoperative chemotherapy is given.
Prophylactic cranial irradiation is usually offered to all patients who have had some
response to therapy, regardless of initial stage, as this confers a survival benefit.43

PROGNOSIS

In the United States, from 2007 to 2013, the overall 5-year relative survival rate was
23.6% for NSCLC and only 7% for SCLC.50 Given these statistics, guidelines recom-
mend that physicians begin discussions about a patient’s prognosis and goals of care
at the time of lung cancer diagnosis, and that they continue such conversations
throughout treatment.51 Particularly for advanced disease, initiation of palliative care
is recommended to be done as early as possible. In fact, there are data to suggest
470 Nasim et al

that the addition of palliation to usual care may prolong survival compared with usual
care alone in addition to improving quality of life.40,52

SUMMARY

Lung cancer remains a highly lethal disease. The implementation of widespread lung
cancer screening holds promise for the future. Given the nonspecific clinical presen-
tation, clinicians should consider the diagnosis in any former or current smoker who
presents with worrisome symptoms. If lung cancer is suspected, referral to a pulmo-
nologist is strongly recommended. There are various minimally invasive diagnostic
and staging modalities currently available and there has been tremendous advance-
ment in our understanding of lung cancer biology leading to various new treatment
options.

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